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Endothelial Overexpression of Transforming Growth Factor Beta Induced in Chronic Thromboembolic Pulmonary Hypertension

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 2Max-Delbrück-Center for Molecular Medicine, Berlin, Germany, Berlin, Berlin, Germany, 3Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases, Clinic of the University of Munich, Germany, München, Bayern, Germany, 4Kerckhoff Heart and Thorax Center, Department of Thoracic Surgery, Bad Nauheim, Germany, Bad Nauheim, Hessen, Germany, 5Center for Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 6University Medical Center Mainz, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany

Abstract Number: OC 56.3

Meeting: ISTH 2022 Congress

Theme: Venous Thromboembolism » Genetic Risk Factors of Thrombosis

Background: Angiogenesis is a critical event during venous thrombus remodeling, and endothelial cell-poor, fibrotic thrombi are obstructing the pulmonary artery lumen in patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Aims: To examine the genetic footprint of endothelial cells from pulmonary thrombofibrotic material to better understand the non-resolution of thrombus and fibrosis.

Methods: Cells outgrown from pulmonary endarterectomy specimens expressing endothelial cell markers (CTEPH-ECs) were processed for whole gene microarray analysis. Spatial laser microdissection followed by nCounter gene expression analysis and immunohistochemistry of tissue microarrays were used to confirm expression of candidate proteins in CTEPH tissue. Plasma levels of candidate genes (TGFBI, TAGLN, FSTL3 and STC2) were examined in CTEPH patients. Finally, lentiviral overexpression of TGFBI was used to assess a role of TGFBI in the process of angiogenesis.

Results: Out of 26,808 genes examined, 527 were differentially regulated in CTEPH-ECs compared to human pulmonary arterial endothelial cells (HPAECs). Biological pathway analysis and RT2 PCR profiler analysis confirmed that factors downstream of transforming growth factor beta (TGFβ) such as TGFβ-induced (TGFBI) or transgelin (TAGLN), or involved in TGFβ signaling such as follistatin-like 3 (FSTL3), were expressed at significantly higher levels in CTEPH-ECs. Spatial laser microdissection followed by nCounter gene expression analysis and immunohistochemistry of tissue microarrays localized potential disease candidates to vessel-rich regions. Whereas circulating levels of TAGLN and FSTL3 were also increased in patients with pulmonary arterial hypertension, only TGFBI plasma levels were specifically elevated in CTEPH patients and found to decrease after pulmonary endarterectomy. Lentiviral overexpression of TGFBI in HPAECs induced the expression of TAGLN, STC2 and the transcriptional repressor SNAI2, thus phenocopying gene expression patterns in CTEPH-ECs.

Conclusion(s): Our findings strengthen the importance of significant endothelial alterations in the pathophysiology of CTEPH and suggest that overexpression of TGFBI in endothelial cells is causally involved in the thrombofibrosis.

To cite this abstract in AMA style:

Bochenek M, Saar K, Nazari-Jahantigh M, Wiedenroth C, Lankeit M, Münzel T, Mayer E, Guth S, Schober A, Hübner N, Konstantinides S, Schäfer K. Endothelial Overexpression of Transforming Growth Factor Beta Induced in Chronic Thromboembolic Pulmonary Hypertension [abstract]. https://abstracts.isth.org/abstract/endothelial-overexpression-of-transforming-growth-factor-beta-induced-in-chronic-thromboembolic-pulmonary-hypertension/. Accessed October 1, 2023.

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